She is most widely known for her portrayal of "Granny" on the long-running TV series The Beverly Hillbillies (1962–1971), for which she was nominated for Emmy Awards for Outstanding Lead Actress in a Comedy Series in 1963 and 1964.

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Commonly thought to have been born in El Paso, Texas, Irene was actually born in San Francisco, California (IMDB entry for Irene Ryan). This is proven by personal records closer to the family, and census records. Ryan was born Jessie Irene Noblitt. She was born to an American father, James Merrit Noblitt, and an Irish immigrant mother, Katherine McSharry.

Before her role as "Granny" on The Beverly Hillbillies, Ryan was an established vaudeville, radio, and movie actress, though not as well known prior to her television stint. Ryan and her first husband, writer-comedian Tim Ryan Tim Ryan, were popular in vaudeville. Their type of double act, known in show business as a "Dumb Dora" routine and epitomized by George Burns and Gracie Allen, had the dizzy woman saying silly things to her boyfriend or husband, and foil. Billed as "Tim and Irene", they had their own series of short subjects in the 1930s for Educational Pictures, and later worked in feature films for Monogram Pictures.

After Tim and Irene divorced, she toured with Bob Hope, making regular appearances on his radio show. In 1946 she married Harold Knox. She continued to work in motion pictures of the late 1940s and early 1950s, generally playing fussy or nervous women. In January 1955, Ryan made her first television sitcom appearance on an episode of CBS's The Danny Thomas Show.[1] Later that same month, she appeared in ABC's Where's Raymond?/The Ray Bolger Show.[2]

In 1962, Ryan was cast as Daisy "Granny" Moses, the matriarch of the Clampett clan, in the CBS-TV comedy series The Beverly Hillbillies. The sitcom ran on the CBS network from 1962 to 1971, and after the show ended Ryan established the Irene Ryan Acting Competition, providing annual scholarships for promising student actors. According to Filmways Publicist Ted Switzer, series creator and producer Paul Henning had decided to cast Bea Benaderet as Granny; however, when Ryan read for the role, “with her hair tied back in a bun and feisty as all get out, she just blew everyone away.” Al Simon (executive producer) and Henning immediately said: “That’s Granny.” Later when Benaderet saw Ryan's tryout, she agreed. Benaderet was then cast as cousin Pearl.[3]

In 1972 Ryan helped to create and also starred in the role of Berthe in the Bob Fosse-directed Broadway musical Pippin (musical), in which she sang the number "No Time At All", which mentions, "a man who calls me Granny." In 1973, Ryan was nominated for Broadway's 1973 Tony Award as Best Supporting or Featured Actress (Musical) for her performance in the musical. She lost to Patricia Elliott (A Little Night Music), in a ceremony held about a month prior to Ryan's death. After Ryan's passing, the role of Berthe was assumed by veteran actress Dorothy Stickney.

In April 1973, Ryan suffered a stroke during a performance of Pippin. Four days after being nominated for a Tony Award for her performance as "Granny" in Pippin, after performing at the Saturday matinee, Ryan flew home to California. She was hospitalized two days later and operated on for a previously undiagnosed brain tumor.
She reportedly was never apprised of the tumor. She died four weeks later, on April 26, 1973 in Santa Monica, California, aged 70.